Due to the rapid rate of worldwide consumption of nonrenewable fossil fuels, production of biofuels from cellulosic sources is receiving increased research emphasis. Here, we review the feasibility to produce lignocellulosic biomass on marginal lands that are not well-suited for conventional crop production. Large areas of these marginal lands are located in the central prairies of North America once dominated by tallgrass species. In this article, we review the existing literature, current work, and potential of two native species of the tallgrass prairie, prairie cordgrass (Spartina pectinata), and little bluestem (Schizachyrium scoparium) as candidates for commercial production of biofuel. Based on the existing literature, we discuss the need to accelerate research in the areas of agronomy, breeding, genetics, and potential pathogens. Cropping systems based on maintaining biodiversity across landscapes are essential for a sustainable production and to mitigate impact of pathogens and pests.